Certain bi-{11 or tricycloalkyl methylbenzenes

ABSTRACT

Compounds such as WHEREIN R3 is bicycloalkyl (C7 to C10) or tricycloalkyl (C10 to C11), useful as intermediates for making N-acylcyclohexylamines of the formula:   WHEREIN R is hydrogen, methyl or ethyl; R1 is hydrogen, or alkyl of 1 through 4 carbon atoms; and R2 is straight chain or branched alkyl of 3 through 8 carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl useful as animal repellants are disclosed, bicycloalkyl, cycloalkylalkyl, or tricycloalkyl. Typical are phenyl-2-(2.2.1)-bicycloheptylmethane, 4cyclobutylmethylbenzoic acid, 4&#39;&#39;-cyclobutylmethylacetophenone, 4-cyclobutylmethylcyclohexane carboxylic acid, and 4-nhexylcyclohexylamine.

United States Patent Knowles [S4] CERTAIN 81- OR TRICYCLOALKYLMETHYLBENZENES [72] inventor: Richard N. Knowles, l-lockessin,

Del.

[73] Assignee: E. I. du Pont de Nemours and Company, Wilmington, Del.

[22] Filed: April 20, 1967 [21] Appl. No.: 635,304

Related US. Application Data [63] Continuation-in-part of Ser. Nos.$74,499, Aug. 18, i966, and Ser. No. 574,276, Aug. l8, 1966.

[52] US. Cl ..260/668 R, 2601514 R, 260/514 B, 260/515 R, 260/56l R,260/563 R, 260/592,

Primary Examiner- Leland A. Sebastian Attorney-Herbert W. Larson [15]3,683,040 1 Aug. 8, i972 [57] ABSTRACT Compounds such as wherein R isbicycloalkyl (C to C or tricycloalkyl (C to C11), useful asintermediates for making N- acylcyclohexylamines of the formula:

R O I ll 1r wherein R is hydrogen, methyl or ethyl; R is hydrogen, oralkyl of 1 through 4 carbon atoms; and R is straight chain or branchedalkyl of 3 through 8 carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl useful as animal repellants aredisclosed, bicycloalkyl, cycloalkylalkyl, or tricycloalkyl. Typical arephenyl-2-[ 2.2. l l-bicycloheptylmethane, 4- cyclobutylmethylbenzoicacid, 4-cyclobutylmethylacetophenone, 4-cyclobutylmethylcyclohexanecarboxylic acid, and 4-n-hexylcyclohexylamine.

1 Claim, No Drawings 1 2 CERTAIN Bl- R TRICYCLOALKYL whereinMETHYLBENZENES R is cycloalkyl of four through nine carbon atoms,CROSSREFERENCE bicycloalkyl of seven through 10 carbon atoms,

cycloalkylalkyl of five through 10 carbon atoms, or This application isa continuation-in-part of U.S. Pat. 5 y y of through 1 1 carbonatomsapplications Ser. No. 574,499, filed Aug. 18, 1966 and Ser. No.574,276, filed Aug. 18, 1966.

U 1. BACKGROUND OFTHEINVENTION """li""""" Application Ser. No. 532,544,filed Mar. 1, I966 h abandoned and a f i alkyl of three throug eightcarbonv atoms :Ziigfiglggfi gg g ag fi gfi giz nng cycloalkyl of fourthrough nine carbon atoms, cycloal- The present application is directedto those kylalkyl of fivethrough l0carbon atoms, bicycloalkyl poundsuseful as intermediates for making the animal g fi l carbon atoms ormcycloalkyl of 10 repellants described in application Ser. Nos. 532,544rough cm H atoms and 574,276.

(0) ll II R C- SUMMARY OFTHEINVENTION 2o 2-H wherein R is hydrogen,methyl or ethyl;

R is alkyl of three through six carbon atoms, cycloalkyl of four throughnine carbon atoms, cycloalkylalkyl of five through 10 carbon atoms,bicycloalkyl of seven through 10 carbon atoms, or tricycloalkyl of 10This invention relates to five classes of intermediates for makingN-acylcyclohexylamines.

More specifically, this invention refers to intermediates forsynthesizing potent animal inhalation irritant compounds of the formula:

( through 11 carbon atoms, with the limitation that the NUR| one andfour groups on the cyclohexyl ring must be in 1 l the cis configuration.z-fi Preparation The animal repellant compounds are prepared using theintermediates of formulas (2) through (6) and the whefem followingsynthetic route:

R15 y 8 b methyl or y R, R, and R, in the following reactions are asdefined R is hydrogen or alkyl of one through four carbon above i f rm latoms; and

R is straight chain or branched alkyl of three through eight carbonatoms, cyclobutyl, cyclohexyl, I if A101, ii cyclopentyl, cycloheptyl,cyclooctyl, cyclononyl, R2001 Q cycloalkylalkyl of five through 10carbon atoms, bicycloalkyl of seven through 10 carbon atoms, or H otricycloalkylof 10 through ll carbonatoms. [Q KOH Q The intermediatecompounds are described in the R20 mm RPCHP following formulas: 4s

. 111 MC] (2) LLQ mom-Q olmicl n on ()CH 2 L'- wherem (1) R isbicycloalkyl of seven through 10 carbon atoms or tricycloalkyl of 10through I 1 carbon atoms. Iv

wherein V Pt R is cycloalkyl of four through nine carbon atoms, R2CHC om3H: m cycloalkylalkyl of five through 10 carbon atoms, 3 2

bicycloalkyl of seven through 10 carbon atoms, or R2OH2 @CO2Htricycloalkyl of 10 through l1 carbon atoms.

v1 H2 S 04 RzCH1--CO H NaN; 01101.1 4

Those compounds where R is methyl or ethyl are prepared according to thefollowing reactions where R; becomes R during react-ion IX.

RgClIr- S Nlllt llCOaClI; rcllux The Friedel-Crafts reaction (I) is runby carefully adding the acid chloride to a stirring mixture of aluminumchloride and benzene. A slight molar excess of catalyst is used; benzeneserves as both a solvent and reactant. The acid chloride is added atsuch a rate so as to keep the temperature of the slurry at about 30-40C. The mixture is stirred for one additional hour after all of the acidchloride is added, and then water is slowly added to decompose thecatalyst. Sufficient water is added so that all the solids aredissolved. The phenylalkyl ketone is isolated from the benzene solutionand is purified by distillation.

The WoliT-Kishner reduction (II) is run in 2-(2- ethoxyethoxy)ethanolusing a modification of the procedure given by J. Cason, et al. inOrganic Synthesis, Collective Vol. IV, John Wiley and Sons, New York,(1963), p. 510. Once the reactants are mixed, they are heated to refluxfor a period of 3 to 5 hours. The reflux temperature is generally in thel30-l40 C. range. After completion of the reflux period, the solution iscooled and poured into 3 to 4 volumes of water. The al- RrCHzeiskylbenzene product is extracted with pentane and purified bydistillation.

The Friedel-Crafts reaction (III) is run by mixing approximatelyequimolar quantities of the reactants together in hexane or nitromethaneat less than 5 C. The stirring mixture is slowly allowed to warm to roomtemperature, and when hydrogen chloride evolution subsides, the mixtureis refluxed several hours. Water is then added slowly to decompose thecatalyst. A sufiicient quantity of water is then added so that all ofthe solids are dissolved. The desired acetophenone derivative isisolated from the organic phase, and purified by distillation.Gas-liquid chromatography on an F & M Model 500 Gas Chromatographerusing a 20 X V4" O.D. stainless steel column, containing 10 percentCarbowax 20M on 60-80 mesh Diatoport T indicates that about 98 percentof the acetophenone is the 1,4 isomer and 2 percent is the 1,2 isomer.The 1,2 isomer has the shorter retention time.

The haloforrn reaction (IV) is run by slowly adding a cold sodiumhypochlorite solution to a stirring solution of the acetophenonederivative in methanol. This is a modification of the procedure used byE. E. Royals (J. Am. Chem. Soc., 69, 841 (1947) for the haloformreaction of a-ionone. After the sodium hypochlorite solution is added,the mixture is warmed to room temperature, and left standing over night.Thereafter, the mixture is heated to reflux, and the distillatecollected until the pot temperature rises to 97C.; most of the methanolis distilled. The pot is then cooled to room temperature. In thosereactions where R has a low molecular weight such as cyclobutyl thesodium benzoate derivative remains dissolved; however, when R becomeslarger, such as bicycloheptyl the sodium benzoate derivativeprecipitates as a soapy solid. Sulfur dioxide is bubbled into thealkaline pot concentrate until the pH drops below 3. The precipitatedbenzoic acid derivative is either filtered and washed with water, orextracted with methylene chloride depending on whether or not thebenzoic acid is easily filterable or is of a soapy nature. Some of thesebenzoic acid derivatives can be recrystallized from acetonitrile orpentane, and some are purified merely by trituration with cold pentane.

The catalytic hydrogenation (V) is performed at two to three atmospheresof hydrogen using platinum oxide as catalyst and glacial acetic acid assolvent. A Parr Hydrogenation Apparatus is suitable for these reactions.This reaction produces a eis/trans isomer mixture of about 2 or 3/ l Thecis and trans designation refers to the relationship of the 4-alkylsubstituent and carboxylic acid group on the cyclohexane ring, this isillustrated below COZH trans The Schmidt reaction (VI) is performed bydissolving the cyclohexane carboxylic acid derivative in a mixture ofchloroform and concentrated sulfuric acid. Sodium azide is then added insmall portions to the stirring mixture at a rate sufiicient to keep thereaction temperature between 35 and 45C. The mixture is stirred at about45 to 50C. until the bubbling nearly stops (1 to 3 hours). The mixtureis then transferred to a separatory funnel, and the lower, gelatinoussulfuric acid layer is slowly dripped onto ice. The amine sulfateprecipitates as a soapy material which slowly crystallizes. Thechloroform should be kept away from the ice water mixture since it makesthe work-up much more difficult. Those amines which crystallize as thehemisulfates or sulfates are filtered and washed with water. It isconvenient to store these amines as their salts. Those amine salts whichfail to crystallize are converted to the free bases by making thesulfuric acid solution alkaline, and extracting the amine withdichloromethane. The amine is then purified by distillation. The Schmidtreaction proceeds without changing the cis/trans product ratio.

The acylation (VII) can be performed by dissolving the free amine in anequal volume of dimethylacetamide (DMAC) or dimethylformamide (DMF) andadding an excess of the desired acid anhydride to the stirring solution.This reaction is very exothermic. The solution is stirred for tenminutes, and then it is poured into to I00 volumes of water. The amideseparates as an oil which subsequently crystallizes.

The acylation (VII) can also be performed using the amine sulfatedirectly according to the following procedure. The amine sulfate isground into a powder, and added to a 1:1 mixture of DMAC and 20 percentaqueous sodium hydroxide solution; there should be a large excess ofbase. The mixture is stirred for 10 to minutes, and then an excess ofthe desired acid anhydride is added. The mixture warms to about 60 to 65C. The sulfate entirely dissolves in 10 to minutes. The solution is thenpoured into 10 to 100 volumes of water. The amide is isolated by theusual procedures given above.

The formamides of reaction VHI are prepared by refluxing the amine withmethylformate for several hours. The excess methylformate is strippedfrom the reaction, and the residual formamide is purified byrecrystallization.

These acylations proceed without changing the cis/trans product ratio.

In those cases where R is methyl or ethyl, the formamide or acetamiderespectively is reduced by lithium aluminum hydride in refluxing etheraccording to reaction IX. The amine is isolated from the reaction afterthe lithium aluminum hydride is destroyed. These amines are purified bydistillation.

Reactions X and XI are run according to the procedures described forreactions VII and VIII respectively.

An alternative synthesis route can be used when the appropriatelysubstituted aniline derivatives are available. This route is illustratedbelow.

XII

The hydrogenation (XH) can be performed at 1 to 3 atmospheres ofhydrogen on a Parr Hydrogenation Apparatus using platinum oxide ascatalyst and glacial acetic acid as solvent. Hydrogen up-take is quiteslow.

The cis/trans ratio of the cyclohexylamine product is about 1:1.

Reactions XIII and XIV are performed according to reactions VII and VIIIdiscussed above. The cis/trans ratio for the amides from XII and XIH isabout 1:1.

The pure amide isomers from reactions VII, VIII, X, XI, XIII and XIV canbe separated by chromatography over silicic acid using methylcyclohexanesaturated with acetonitrile as the eluting solvent. Isomer mixtures alsocan be separated by gas-liquid chromatography using 10 percent Carbowax20M on 60-80 mesh Diatoport T. In both of these chromatography methods,the cis isomer elutes before the trans isomer. The cis amine isomer canbe regenerated by alkaline hydrolysis of the purified amide.

The following additional examples describe the invention in greaterdetail.

EXAMPLE 1 A 23.9 gram quantity of 4-n-butylaniline (from AldrichChemical Company) is dissolved in 250 milliliters of glacial aceticacid, and 1 gram of Adams Catalyst (PtO is added. The mixture is thenhydrogenated at two to three atmospheres using a Parr HydrogenationApparatus. To insure complete reduction, the hydrogenation is run overnight. The catalyst is then filtered, and the acetic acid is removedunder reduced pressure on a steam bath. The concentrate is taken up inether and washed with dilute, aqueous sodium bicarbonate. The etherealsolution is dried (MgSO filtered and evaporated in vacuum leaving 21grams of the 4-nbutylcyclohexylamine (n 1.4574). The amine is taken upin two volumes of dirnethylacetamide and treated with one volume ofacetic anhydride. The temperature of the stirring solution rises rapidlyto 60-80 C. After having stirred for ten minutes, the solution is pouredinto 10 volumes of water. The oil which separates is extracted withether. The ethereal solution is dried (MgSO filtered and strippedleaving an oil which slowly crystallizes. This waxy solid softens at57C. and melts from 79100C. Gas-liquid chromatography of this cis/transmixture of N-acetyl-4-nbutylcyclohexyl-amine on an F & M Model 500 GasChromatograph over 10 percent Carbowax 20M on 60-80 mesh Diatoport T ina A." X 2' stainless steel column at a temperature of 200 C., a blocktemperature of 308C, and an injection port temperature of 280C. with aHe flow rate of 60 cc./min. shows that the cisztrans ratio is about 1 :1

The retention times for the cis and trans isomers are 28.0 and 32.5minutes respectively. The cis isomer causes severe burning of theoperators nose as it elutes from the column while the trans isomer doesnot cause much irritation.

XIII

DMAC

The infra-red spectrum (nujol) for this mixture shows characteristicpeaks at 3300 cm" for the N-H, 1630 and 1560 cm for the amide carbonyl,1320 cmfor the trans isomer and 1280 cm" for the cis isomer. Anal.Calcd. for C H NO: C, 73.0; H, 11.8; N, 7.1%

Found: C, 72.9; H, 11.7; N, 6.7%

Mice are treated by aerosol exposure to the cis/trans mixture ofN-acetyl-4-n-butylcyclohexylamine (c) in the following manner: Thecompound is administered as an aerosol into a 2.8 liter chamber. Theexposure chamber consists of a 2.8 liter bell jar over a nebullizerinserted through the floor of the chamber. Mice are exposed for fiveminutes to 200.0 micrograms per liter (1,000Ct). The compound isdissolved in 1.4 ml. of acetone and during a span of 20 seconds thecompound is sprayed up into the chamber. No further air is transferredinto or out of the chamber during the 5 minute exposure.

After this exposure, irritant effects are observed in all mice exposed.The mice used as controls exposed to 1.4 ml. of acetone alone exhibit noirritant effects. Irritant effects can be described as the presence ofone or more of the following reactive signs:

a. hyperemia of the ears, nose and tail b. abnormal gait, includingrubbing of the nose on the floor while running about c. blinking d.salivation e. depression f. dyspnea g. hunched posture h. facepawing.

EXAMPLE 2 A mixture consisting of 400 ml. of benzene and 67 g. (0.5mole) of aluminum chloride is stirred in a one liter round bottom flaskfitted with a stirrer, thermometer condenser connected to a scrubber,dropped funnel, and cooling bath. Cyclobutane carbonyl chloride (50 g.;0.42 mole) is added dropwise while the pot temperature is held below 35C. The brown slurry is stirred for 1 hour and then water is cautiouslyadded while the pot temperature is held below 30 C. Sufficient water isadded so that all the solids dissolve. Two liquid phases are obtained.The mixture is transferred to a separatory funnel, and the benzene layeris separated. The aqueous layer is washed with 100 ml. of benzene whichis then combined with the first benzene fraction. The aqueous solutionis discarded. The combined benzene fractions are washed sequentiallywith 200 ml. of 5 percent aqueous sodium hydroxide solution and 250 ml.of water. The benzene solution is dried with magnesium sulfate,filtered, and evaporated in vacuum. The residual oil is distilled at 67C. at 0.1 mm. of mercury giving cyclobutylphenylketone (11,, 1.5455).

Anal. Calcd. for C H O: C, 82.5; H, 7.6%

Found: C, 81.9; H, 7.6%

EXAMPLES 3 5. 3-Cyclopentylpropiophenone: B 1.5300 Anal. Calcd. for CI-1 0: C, 83.2; H, 8.9%

Found: C, 83.1; H, 8.9% 6. Cycloheptylphenylketone: B 134-136C.; n1.5415 7. l-Adamantylphenylketone: m. 49-52C. 8.2-[2.2.2]-Bicyclooctylphenylketone 9. 1-[3.2.1]-Bicyclooctylphenylketone 10. 2-[ 3.3. 1 ]-BicyclononylphenylketoneEXAMPLE 11 A solution of potassium hydroxide (140g; 2.5 mole) in 500 ml.of 2-(2-ethoxyethoxyl)ethanol (from Matheson, Coleman & Bell Co.) isprepared by carefully heating the mixture until all of the solids aregone. The solution is cooled to below C. Then 2-[2.2.1bicycloheptylphenylketone (94.7g.; 0.50 mole) and 99 percent hydrazinehydrate (1 10 g.; 2.2 mole) are added all at once. The reactants arerefluxed for 4 hours at 135 C., and then the solution is poured into 2.5l. of water. The oil which separates is extracted with three- 500 ml.portions of pentane. The aqueous phase is discarded, and the combinedpentane fractions are dried with magnesium sulfate, filtered andevaporated in vacuum. The residual oil is distilled at C. at 12 mm. ofmercury to give phenyl-2-[2.2.l]-bicycloheptylmethane (n 1.5342).

Anal. Calcd. for C I-1, C, 90.3; H, 9.7%

Found: C, 90.8; H, 9.5%

EXAMPLES 12 22 The following phenylmethane derivatives are preparedaccording to the procedure given for phenyl-2-[2.2.1]-bicycloheptylmethane in Example 8 by substituting the likemolar amount of the appropriate phenylketone for 2-[2.2. l]-bicycloheptylpheny1ketone of Example 8.

12. Isobutylbenzene: B 168C; n 1.4800.

13. Cyclobutylphenylmethane: B 89C.; n 1.5150.

14. Cyclopentylphenylmethane: B 92C.; n 1.5165.

EXAMPLE 23 A solution of cyclobutylphenylmethane (20.5 g.; 0.14 mole)and acetyl chloride (12.5 g.; 0.16 mole) in 400 ml. of hexane is cooledto 0C. and aluminum chloride (21.5 g.; 0.16 mole) is added all at once.The reaction equipment is similar to that given in Example 2. Thestirring mixture is warmed to about 5 C., and held there for one-halfhour. The slurry is then warmed to room temperature for 1 hour, andfinally refluxed for 30 minutes. Water is then carefully added todecompose the aluminum chloride. Sufficient water is finally added todissolve all the solids and obtain two liquid phases The mixture istransferred to a separatory funnel, and the hexane solution is isolated.The aqueous phase is washed with 100 ml. of hexane, and then discarded.The combined hexane fractions are washed sequentially with 100 ml. ofpercent aqueous sodium hydroxide solution and 100 ml. of water. Thehexane solution is dried with magnesium sulfate, filtered and evaporatedin vacuum. The residual oil is distilled at 108C. at 1 mm. of Hg to give4'-cyclobutylmethylacetophenone (n 1.5388).

Anal. Calcd. for C H O: C, 82.9; H, 8.6%.

Found: C, 83.1; H, 8.5%.

The pertinent features in the infra-red spectrum are a very strong peakat 1680 cm (carbonyl) and a peak at 850 cmindicative of two adjacentbenzenoid hydrogens thus showing that the benzene ring has substituentsin the 1 and 4 positions.

A gas-liquid chromatograrn obtained on an F & M Model 500 GasChromatograph using a 2' X W O.D. Stainless Steel column packed withpercent Carbowax 20M on 60-80 mesh Diatoport T with a helium flow rateof 60cc/min. a block temperature of 307 C., an injection porttemperature of 262 C., and a column temperature of 225 C. shows that thesample consists of 98 percent of the 1,4-isomer and 2 percent of the1,2-isomer which have retention times of 9.5 and 8.0 minutesrespectively.

EXAMPLES 24-42 The following acetophenone derivatives are preparedaccording to the procedure given for 4' cyclobutylmethylacetophenone inExample 23 by substituting a like amount of the appropriatealkylphenylmethane derivative for the cyclobutylphenylmethane of Example23. For those compounds where R, is bi-or tricycloalkyl, nitromethanecan be used as solvent in place of the hexane. The infra-red spectra forall these compounds are similar to that reported for4'-cyclobutylmethylacetophenone in Example 23.

24. 4-Isobutylacetophenone: B 110 C.; n,, 1.5 6.

25. 4'-n-Pentylacetophenone: l3 122 C.; n 1.5142.

26. 4'-Cyclopentylmethylacetophenone: B 130- 1 32 C.;

Calcd. for C I-1, 0: C, 83.2; H, 8.9%. Found: C, 83.5; H, 8.9%.

Gas-liquid chromatography under conditions like those in Example 23 at acolumn temperature of 200 C. gives peaks at 14.0 minutes (2 percent ofsample) for the 1,2-isomer at 17.5 minutes (98 percent of sample) forthe 1,4-isomer.

27. 4'-(2-Methylpentyl)acetophenone: B 96 C.; n,, 1.5120. Anal. Calcd.for C I-I 0: C, 82.3; H, 9.9%.

Found: C, 82.2; H, 9.8%.

Gas-liquid chromatography under conditions like those in Example 23gives peaks at 6.0 minutes (1 percent of sample) for the l,2-isomer and7.5 minutes (99 percent of sample) for the 1,4-isomer.

28. 4'-n-Hexylacetophenone: "D251 .5 106. 29.4-Cyclohexy1methylacetophenone. 30. 4'-n-l-leptylacetophenone: B -134C.;n 1.5084. 31. 4'-n-Octylacetophenone: B 128C.; n 1.5060. 32. 4'-(3-Cyclopentylpropyl)acetophenone: B 154C; n 1.5298. Anal. Calcd. for C HO: C, 83.5; H, 9.6%.

Found: C, 83.5; H, 9.6%. 33. 4'-Cycloheptylmethylacetophenone: B 136-140C; 11,, 1.5426. Anal. Calcd. for C l'l O: C, 83.4; H, 9.6%.

Found: C, 83.6; H, 9.7%. 34. 4'-Cyclononylmethylacetophenone. 35.4-Cyclooctylmethylacetophenone. 36. 4'-( 2-[2.2.1]-Bicycloheptylmethyl)acetophenone: B 117C.;n 1.5511. Anal. Calcd. forCml-l O: C, 84.2; H, 8.8%.

Found: C, 84.1; H, 8.8%.

Gasliquid chromatography under conditions like those given in Example 23gives a single peak with a retention time of 29.5 minutes.

37. 4-( l-Adamantylmethyl)acetophenone.

38. 4'-( 2-[ 2.2.2]-Bicyclooctylmethy1)acetophenone. 39. 4'-( 1-[3.2. l]-Bicyclooctylmethyl)acetophenone. 40. 4'-(2-[ 3.3. l]-Bicyclononylmethyl)acetophenone. 4 1 4-( 1-Homoadamantylmethyl)acetophenone.

42. 4'-( 2-[ 3.2.01-Bicycloheptylmethyl )acetophenone.

EXAMPLE 43 A solution of 4'-cyclobutylrnethylacetophenone (20 g.; 0.11mole) in 225 ml. of methanol is cooled to less than 5C., and 275 ml. ofa 1.29M sodium hypochlorite solution (0.35 moles) is slowly added. Thetemperature is held below 5 C. during the addition. The sodiumhypochlorite solution is conveniently prepared according to theprocedure given by M. S. Newman, Organic Synthesis, Collective Volume11, John Wiley and Sons, New York, 1943, p. 429. After about 25 ml. ofthe hypochlorite solution is added, a white precipitate forms. When allof the hypochlorite solution is added, the stirring mixture is allowedto warm to room temperature, and left standing over night. Somechloroform usually separates during the night. The stirring mixture isheated to reflux 80 C.) and distillate 200 ml.) is collected until thepot temperature rises above 95 C. The pot concentrate is cooled to roomtemperature, and sulfur dioxide is bubbled into it until the pH fallsbelow 3. The precipitate is extracted with two-300 ml. portions ofdichloromethane, and the aqueous phase is discarded. The combineddichloromethane solutions are dried with magnesium sulfate, filtered andevaporated in vacuum. The yellow residue is triturated with coldpentane, and filtered. The 4-cyclobutylmethylbenzoic acid melts at146149 C. and has an infra-red spectrum showing typical benzoic acidabsorption peaks.

Anal. Calcd. for C H O C, 75.8; H, 7.4%.

Found: C, 75.5; H, 7.6%.

Calcd. neutral equivalent weight:

Found: 198

EXAMPLES 44 62 The following 4-alkylbenzoic acid derivatives areprepared according to the procedure given for 4- cyclobutylmethylbenzoicacid in Example 43 by substituting the appropriate 4'-alkylacetophenonein a like molar amount for the 4-cyclobutylmethylacetophenone of Example43. All of these compounds show the typical benzoic acid absorptionpeaks in their infra-red spectra.

44. 4'-Isobutylbenzoic acid: m. 143.0144.5 C. Anal. Calcd. for C H O C,74.2; H, 7.9%.

Found: C, 74.2; H, 7.9%. 45. 4-n-Pentylbenzoic Acid: m. 87.0-88.5 C. 46.4-Cyclopentylmethylbenzoic acid: in. 143.0145.0 C. Anal. Calcd. for C HO C, 76.5; H, 7.9%

Found: C, 76.1; H, 7.5%. 47. 4-(2-Methylpentyl)benzoic acid: m. 103-1 C.Anal. Calcd. for C H O :C, 75.7; H, 8.8%.

Found: C, 75.9; H, 8.9%. 48. 4-n-Hexylbenzoic acid. m. 7782 C. 49.4-Cyclohexylrnethylbenzoic acid. 50. 4-n-Heptylbenzoic acid: m. 9396C.51. 4-n-0ctylbenzoic acid: m. 96-98C. 52. 4-(3-Cyclopentylpropyl)benzoicacid: in 1 l7-1 19 C. Anal. Calcd. for C H O z C, 77.5; H, 8.7%.

Found: C, 77.6; H, 8.7%. 53. 4-Cycloheptylmethylbenzoic acid: m.171-l73C. Anal. Calcd. for C H O z C, 77.5; H, 8.7%.

Found: C, 77.2; H, 8.7%. 54. 4-qyclooctylmethylbenzoic acid. 55.4-Cyclononylmethylbenzoic acid. 56.4-(2-[2.2.1]-Bicycloheptylmethyl)benzoic acid: m. l71173C. Anal. Calcd.for C H O :C, 78.3; H, 7.9%

Found: C, 77.6; H, 7.9%. Calcd. neutral equivalent weight: 230.

Found: 243. 57. 4-(1-Adamantylmethyl)benzoic acid. 58.4-(2-[2.2.2]-Bicyclooctylmethyl)benzoic acid. 59. 4-( 1-[ 3.2. l]-Bicyclooctylmethy1 )benzoic acid. 60. 4-(2-[3.3. 1]-Bicyclononylmethy1)benzoic acid. 61. 4-( l-Homoadamantylmethyl)benzoicacid. 62. 4-(2-[ 3 .2.0]-Bicycloheptylmethyl)benzoic acid.

EXAMPLE 63 A sample of 4-cyclobutylmethylbenzoic acid (8.3 g.; 0.044mole) is dissolved in 250 ml. of glacial acetic acid in a 500 ml.pressure bottle and platinum oxide (1 g.) is added. The mixture is thenshaken under a hydrogen pressure of 45 p.s.i.g. on a Parr HydrogenationApparatus for 24 hours; the final pressure is 33 p.s.i.g. The catalystis filtered, and the acetic acid removed in vacuum. The residual oil istaken up in 200 ml. of ether, and washed with two-100 ml. portions ofwater to remove the residual acetic acid. The ethereal solution is thendried with magnesium sulfate, filtered and evaporated in vacuum leavingan oil which subsequently crystallizes. The4-cyclobutylmethylcyclohexane carboxylic acid is recrystallized from amixture of ethanol and water, and melts from 59 to 69 C. The cis/transmixture of carboxylic acids causes the broad melting range.

Anal. Calcd. for C I-1 0 C, 73.5; H, 10.2%.

Found: C, 73.4; H, 10.2%. The infra-red spectrum shows that the benzenering has been reduced.

EXAMPLES 64 82 The following 4-alkylcyclohexane carboxylic acidderivatives are prepared according to the procedure given for4-cyclobutylmethylcyclohexane carboxylic acid in Example 63 bysubstituting the appropriate 4- alkyl-benzoic acid in a like molaramount for the 4- cyclobutylmethylbenzoic acid of Example 63. Infra-redspectra of these compounds also show that the benzene rings have beenreduced.

64. 4-Isobutylcyclohexane carboxylic acid: B 118- 119C.;n 1.4638. Anal.Calcd. for C H O C, 71.7; H, 10.9%

Found: C, 72.3; H, 11.3%. 65. 4-nPentylcyclohexane carboxylic acid: B138 C.; n 1.4652. Anal. Calcd. for C H O- C, 72.8; H, 1 1.2%.

Found: C, 72.8; H, 11.4%. 66. 4-Cyclopentylmethylcyclohexane carboxylicacid; B 140 C.; n 1.4910, m. 38-47 C. Anal. Calcd. for C H O C, 74.2; H,10.5%

Found: C, 73.9; H, 10.7%. 67. 4-(2-Methylpentyl)cyclohexane carboxylicacid: B03 126 -130 H025 Anal. Calcd. for C H O C, 73.5; H, 11.3%.

Found: C, 73.8; H, 11.2%. 68. 4-n-Hexylcyclohexane carboxylic acid: B129- l31C.;n 1.4666. Anal. Calcd. for C H O C, 73.4; H, 11.4%.

Found: C, 74.0; H, 11.1%. 69. 4-Cyclohexylmethylcyclohexane carboxylicacid: m. 62-69 C. Anal. Calcd. for C H O C, 74.9; H, 10.8%.

Found: C, 75.2; H, 10.7%. 70. 4-n-Heptylcyclohexane carboxylic acid: BC.; n,, 1.4676. Anal. Calcd. for C H O C, 74.3; H, 1 1.6%.

Found: C, 74.5; H, 11.4%. 71. 4-n-Octylcyclohexane carboxylic acid: m.3639 C. (from acetonitrile) Anal. Calcd. for C H O z C. 75.0; H, 11.4%.

Found: C, 75.5; H, 11.9%. 72. 4-(3-(b'clopentylpropyl)cyclohexanecarboxylic acid: B05 D25 Anal. Calcd.for C H o C, 75.5; H, 11.0%.

Found: C, 75.4; H, 10.8%. 73. 4-Cycloheptylmethylcyclohexane carboxylicacid; B 160-162 C.; n 1.4963; m. 45-49 C. Calcd. for C H O z C, 75.5;H,11.0%. Found: C, 75.5; H, 10.8%. Neutral Equivalent: Calcd. 238. Found:238. 74. 4-n-Nonylcyclohexane carboxylic acid. 75.4-Cyclononylmethylcyclohexane carboxylic acid. 76. 4-(2-[2.2. 1]-Bicyclohepty1methyl)cyclohexane carboxylic acid: m. 6473 C. (fromethanol). Anal. Calcd. for G i-1 0 C, 76.2; H, 10.2%.

Found: C, 76.1; H, 10.1%. 77. 4-(1-Adamantylmethyl)cyclohexanecarboxylic acid. 78. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexanecarboxylic acid. 79. 4-(1-[3.2.1 ]-Bicyclooctylmethyl)cyclohexanecarboxylic acid. 80. 4-(2-[3.3.1]-Bicyc1ononylmethyl)cyclohexanecarboxylic acid.

81. 4-( 1-l-lomoadamantylmethyl)cyclohexane carboxylic acid.

82. 4-(2-[3.2.0]-Bicycloheptylmethyl)cyclohexane carboxylic acid.

EXAMPLE 83 A sample of 4-n-hexylcyclohexane carboxylic acid (24 g.; 0.11mole) is taken up in a mixture of 200 ml. of chloroform and 1 10 ml. ofconcentrated sulfuric acid in a 500 ml. Erlenmeyer flask. Sodium azide(9.8 g.; 0.15 mole) is carefully added with a spatula at a rate to keepthe temperature of the stirring mixture between 35 and 45 C. Aftercompletion of the sodium azide addition, the stirring mixture is heatedat 45-50C. for 2 hours; the rate of gas evolution is very slow at thistime. The mixture is transferred to a separating funnel and the lower,gelatinous sulfuric acid layer is slowly dripped into one liter ofcrushed ice. The 4-n-hexylcyclohexylamine hemisulfate crystallizesslowly. The salt is filtered and washed with water; it is almostcompletely insoluble in water. The melting point is above 300 C.

Anal. Calcd. for C, H N%H SO C, 62.1; H, l 1.3; N, 6.0; S, 6.9%.

The infra-red spectrum shows absorptions characteristic of amine saltsand sulfates and has no absorption corresponding to a carboxyl function.

EXAMPLES 84 102 The following 4-alkylcyclohexylamine derivatives ortheir salts are prepared according to the procedure given for4-n-hexylcyclohexylamine hemi-sulfate in Example 83 by substituting theappropriate 4-alkylcyclohexane carboxylic acid in like amount by weightfor the 4-n-hexylcyclohexane carboxylic acid of Example 83. In thoseinstances where the free amines are prepared, the amine salt isdissolved in 10 percent aqueous sodium hydroxide solution, and the freeamine is extracted with dichloromethane. The dichloromethane solution isdried with magnesium sulfate, filtered and evaporated in vacuum. Theresidual oil is distilled in vacuum through a spinning band column. Theinfra-red spectra of these compounds all show the loss of the carbonylfunction and the presence of an amino function.

84. 4-Isobutylcyclohexylamine: B 56 C.; n 1.4552.

Anal. Calcd. for C H N: C, 77.4; H, 13.6; N, 9.0%.

Found: C, 77.6; H, 13.5; N, 9.1%.

85. 4-n-Pentylcyclohexylamine: B 76 C.; a

Anal. Calcd. for C H N: C, 78.0; H, 13.7; N, 8.3%.

Found: C, 77.9; H, 13.6; N, 8.6%.

86. 4-Cyclopentylmethylcyclohexylamine hemi-sulfate:

Anal. Calcd. for C, H N%H SO,: C, 62.6; H, 10.5; N,

Found: C, 62.0; H, 10.7; N, 6.0%.

87. 4-(2-Methylpentyl)cyclohexylamine: B 80-81 Anal. Calcd. for C H N:C, 78.7; H, 13.7; N, 7.6%.

Found: C, 78.3; H, 13.7; N, 8.1%.

88. 4-Cyclobutylmethylcyclohexylamine.

89. 4cis-Cyclohexylmethylcyclohexylarnine sulfate: m. 300C.

Anal. Calcd. for C, H N%H S C, 64.0; H, 10.8; S,

hemi- Found: C, 63.9; H, 10.6; S. 6.9%. 90. 4-n-Heptylcyclohexylaminehemi-sulfate hemihydrate: m. 300 C. Anal. Calcd. for C, H N%H,S0,%H O:C, 62.3; H, 1 1.5; N, 5.6% Found: C, 62.6; H, 12.0; N, 5.0%. 91.4-n-Octylcyclohexylamine hemi-sulfate hemihydrate. Anal. Calcd. for C HN%H SO %H O: C, 62.4; H, 11.6; N, 5.2%.

Found: C, 61.8; H, 12.0; N, 5.1%. 92.4-(3-Cyclopentylpropyl)cyclohexylamine sulfate: m. 300C. Anal. Calcd.for C H N-H SO C, 54.6; H, 9.5; N, 4.6; S, 10.4%.

Found: C, 55.2; H, 9.8; N, 4.5; S. 9.9%.

93. 4-Cycloheptylmethylcyclohexylarnine hemi-sulfate: m 300 C. 94.4-Cyclooctyhnethylcyclohexylamine hemi-sulfate: m 300 C. 95.4-Cyclononylmethylcyclohexylarnine hemi-sulfate: m 300C. 96. 4-(2'[2.2.l ]-Bicycloheptylmethyl)cyclohexylami ne hemi-sulfate dihydrate: m. 300C. Calcd. for C14H25NC14H25N'5QH2S04'2H201 C, H, N, 4.8%. Found: C,58.5; H, 9.3; N, 4.7%. 97. 4-(1-Adamantylmethyl)cyclohexylamine sulfate:m. 300B C. 98. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexylamine sulfate:m. 300 C. 99. 4-( l-[3.2.1 ]-Bicyclooctylmethyl)cyclohexylarninesulfate: m. 300 C. 100. 4-(2-[3.3.1 ]-Bicyclononylmethyl)cyclohexylamine hemi-sulfate: m. 300 C. 101 4-( l-Homoadamantylmethyl)cyclohexylaminesulfate: m. 300 C. 102. 4-(2-[3.2.0]-Bicycloheptylmethyl)cyclohexylamine hemi-sulfate: m. 300 C.

EXAMPLE 103 A sample of 4-n-hexylcyclohexylamine hemi-sulfate (10 g.;0.043 mole) is stirred for ten minutes in a mix- 5 ture consisting of100 ml. of dimethylacetamide and 25 ml. of 20 percent aqueous sodiumhydroxide solution. Acetic anhydride (20 ml.) is added with stirring;the temperature rises to -80 C. After the temperature has dropped toabout 60 C., the milky suspension is filtered to remove any traces ofunreacted 4-n-hexylcyclohexylamine hemi-sulfate. The milky filtrate ispoured into 1200 ml. of water, and the oil which separates crystallizes.The crystalline N-acetyl-4-n-hexylcyclohexylamine is filtered and washedwith water. It melts from 49 to 87 C.

Anal. Calcd. for C H NO: C, 74.8; N, 12.1; N, 6.2%.

Found: C, 74.7; H, 12.0; N, 6.3%.

Gas-liquid chromatography on an F & M Model 500 Gas Chromatograph usinga 2' X V4" O.D. stainless steel column packed with 10 percent Carbowax20M on 60-80 mesh Diatoport T at a column temperature of 200 C., a blocktemperature of 308 C. an injection port temperature of 265 C. and ahelium flow rate of 60 cc/min. shows that the sample consists of twocompounds present to the extent of 64 and 36 percent which haveretention times of 53.3 and 61.8 minutes respectively.

A nuclear magnetic resonance spectrum of the mixture shows that thelarger component is N-acetyl-cis-4- n-hexylcyclohexylamine and thesmaller component is N-acetyl-trans-4-n-hexylcyclohexylamine.

The pure isomers are isolated by adsorption chromatography over silicicacid using methylcyclohexane saturated with acetonitrile as the elutingsolvent; the adsorbant to compound ratio is 50: 1.N-Acetyl-cis-4-nhexylcyclohexylamine melts at 550 to 57.0 C., andN-acetyl-trans-4-n-hexylcyclohexylamine melts at 123.0-124.0 C.

The cis/trans mixtures are used for the purposes of this inventionwithout separation of the isomers.

N-Acetyl-4-n-hexylcyclohexylamines are used to treat mice according tothe procedures given in Example l with like results. At the time miceare treated in such manner with the pure isomers, the cis isomer isshown to be much more of an irritant than the trans isomer.

EXAMPLES 104 125 The following N-acyl-4-alkylcyclohexylamines areprepared according to the procedure given for N-acetyl-4-n-hexylcyclohexylamine in Example 103 by substituting in a likemolar amount the appropriate 4- alkylcyclohexylamine and acid anhydridefor the 4-nhexylcyclohexylamine and acetic anhydride of Example 103.

104. N-Acetyl-4-isobutylcyclohexylamine: m. 961 18 C. cis/trans ratio63(41.0 min.)/37 (47.2 min.) by G.L.C. method like that in Example 103at a column temperature of 180 C.

Anal. Calcd. for C, H NO: C, 73.0; H, 11.7; N, 7.1%. Found: C, 73.1; H,12.2; N, 7.0%.

1 N-Butyryl-4-isobutylcyclohexylamine.

106. N-Acetyl-4-n-pentylcyclohexylamine: m. 4595 C. cis/trans ratio68(34.3min.)/32(39.9min.) by G.L.C. method like that in Example 103 at acolumn temperature of 200 C.

Calcd. for C H NO: C, 75.0; H, 1 1.9; N, 6.6%. Found: C, 73.6; H, 12.3;N, 6.6%.

107. N-Propionyl-4-n-pentylcyclohexylamine.

108. N-Acetyl-4-cyclopentylmethylcyclohexylamine: m. 65-78 C. cis/transratio 74(33min.)/26(37min.) by G.L.C. method like that in Example 103 ata column temperature of 225 C.

Calcd. for C H NO: C, 75.4; H, 1 1.2; N, 6.2%. Found: C, 75.2; H, 11.4;N, 6.2%.

109. N-Propionyl-4-cyclopentylmethylcyclohexylamine.

110. N-Acetyl-4-(2-methylpentyl)cyclohexylamine: m. 5869 C. cis/transratio 87(54.5min.)/13(62.6min.) by G.L.C. method similar to that inExample 103 at a column temperature of 190 C.

Calcd. for C H NO: C, 74.7; H, 12.1; N, 6.2%. Found: C, 74.6; H, 11.9;N, 6.0%.

1 l 1. N-Acetyl-4-Cyclobutylmethylcyclohexylamine: m. 4259 C. cis/transratio 78(43.5min)/ 22(49.6min) by a G.L.C. method like that in Example103 at a column temperature of 200 C.

Calcd. for C H NO: C, 74.7; H, 11.1; N, 6.7%. Found: C, 74.7; H, 11.1;N, 6.5%.

1 l2. N-Acetyl-4-n-heptylcyclohexylamine; m. 611 14 C., cis/trans ratio64(23.5min.)/36(27.0min.) by a G.L.C. method like that in Example 103 ata col. temperature of 230 C.

Calcd. for C ,H NO: C, 75.3; H, 12.2; N, 5.9%. Found: C, 75.0; H, 12.1;N, 5.9%.

113. N-Acetyl-4-n-octylcyclohexylamine; m. 62-82 C. cis/trans ratio(31.5min.)/25(36.5min.) by a G.L.C. method similar to that of Example 112.

Calcd. for C H NO: C, 76,0; H, 12.3; N, 5.5%. Found: C, 75.8; H, 12.3;N, 5.4%.

1 17. N-Acetyl-4-cyclooctylmethylcyclohexylamine.

1 18. N-Acetyl-4-cyclononylmethylcyclohexylamine.

1 19. N-Acetyl-4-( 2-[2.2.1 l-bicycloheptylmethyl)cyclohexylamine: m.1111 13 C. cis/trans ratio 73(55.8min.)/27(63.5min.) by G.L.C. methodlike that in Example 103 at a column temperature of 225C.

Calcd. for C H NO: C, 77.2; H, 10.9; N, 5.6%. Found: C, 76.9; H, 10.7;N, 5.6%.

120. N-Acetyl-4-( 1-adamantylmethyl)cyclohex ylamine. 121.N-Acetyl-4-(2-[ 2.2.21-bicyclooctylmethyl)cyclohexylamine.

122. N-Acety1-4-( 2-[ 3.2.1 ]-bicyclooctylmethyl)cyclohexylamine.

123. N-Acetyl-4-(2-[ 3.3. l l-bicyclononylmethyl)cyclohexylamine. 124.N-Acetyl-4-( 1-homoadamantylmethyl)cyclohexylamine. 125. N-Acetyl-4-(2-[3.2.0 l-bicycloheptylmethyl)cyclohexylamine.

EXAMPLE 126 A sample of 4-cyclobutylmethylcyclohexylamine (20 g.; 0.060mole) is refluxed for 3 hours with 20 ml. of methylformate. The solutionis then evaporated in vacuum and the residualN-formyl-4-cyclobutylmethylcyclohexylamine is purified byrecrystallization from hexane. ThisN-formyl-4-cyclobutylmethylcyclohexylamine is used to treat mice andother animals according to the procedures given in U.S. Pat. applicationSer. No. 532,544, filed Mar. 1, 1966 now abandoned.

EXAMPLE 127 A mixture of N-formy1-4-cyclohexylmethylcyclohexylamine(7.9g.; 0.035 mole) and lithium aluminum hydride (LAH) (3.8g; 0.10mole)is heated in ml. of refluxing ether for 24 hours. The suspension iscooled, and the lithium aluminum hydride is decomposed using wet etherand then a saturated, aqueous solution of sodium sulfate. Thisdecomposition should be performed cautiously to avoid a fire. The

' precipitated salts are filtered and washed with ether.

The ethereal solution is then dried with magnesium sulfate, filtered andevaporated in vacuum learving an oil. The infra-red spectrum shows theoil to be an amine. The N-methyl-N-cyclohexylmethylcyclohexylamine ispurified by vacuum distillation.

EXAMPLES 128-141 The following dialkylamines are prepared according tothe procedure described for N-methyl-N-cyclohexylmethyl-cyclohexylaminein Example 127 by substituting in like amount by weight the appropriateN-fonnyl or N-acetyl-4-alkylcyclohexylamine for the N-formyl-N-cyclohexylmethyl-cyclohexylamine in Example 127. 128.N-Methyl-N-(4-cyclobutylmethylcyclohexyl)amine.

129. N-Ethyl-N-(4-n-butylcyclohexyl)amine.

